Genetic counselling and testing in pulmonary arterial hypertension:a consensus statement on behalf of the International Consortium for Genetic Studies in PAH

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.</p

CTEPH medical treatment options and guidelines

Chapter in Educational Handbook for Hospital Pharmacy Europe www.hospitalpharmacyeurope.comstatus: publishe

Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience

Macitentan (10 mg once daily orally), a dual endothelin receptor antagonist (ERA) developed by modifying the structure of bosentan to increase the efficacity and safety, is approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal SERAPHIN trial, (a landmark trial in the history of PAH trials because of the large number of included patients, the long-term follow up and the first trial with morbidity/mortality as the primary endpoint) showed a reduction of the risk of a morbidity or mortality event by 45% over the treatment time compared with placebo. The positive effect on the primary endpoint was observed whether or not the patient was already on PAH therapy. There has been no direct comparison between macitentan and other ERAs, which were approved based on improved exercise capacity, but preclinical and clinical data suggest better pharmacological and safety profiles. Further analyses of the SERAPHIN trial investigated the predictive value of different indices and events on long-term outcome and mortality. The efficacy in children, the long-term effects and safety of macitentan and its place in combination therapy compared with other ERAs are still under investigation. This review presents the preclinical evidence of superiority of macitentan compared with other ERAs, and the available clinical trial data. The place of macitentan in the therapeutic algorithm for PAH treatment, post-marketing experience and future perspectives are discussed

Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Model

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Health-related quality of life and socio-economic correlates in patients with pulmonary arterial hypertension

Pulmonary Arterial Hypertension (PAH) imposes a substantial burden on individuals with the disease. The symptoms of PAH are unspecific and of varying severities; breathlessness, fatigue, edema of the lower limbs, dizziness and syncope. The importance of measuring the associated impact on health-related quality of life (HRQoL) is increasingly recognized and new instruments are available. This article reviews the validation and use of recently published questionnaires to evaluate HRQoL in PAH, the economic burden of PAH and new evidence in non-pharmacological supportive treatments.status: publishe

TGF and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a severe condition characterised by remodelling of precapillary pulmonary arteries sometimes associated with mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene. Even in the absence of BMPR2 mutations, increased transforming growth factor (TGF)β receptor signalling and decreased BMPRII signalling have been shown to contribute to PAH pathogenesis. In this Keynote, we review the potential mechanisms by which the imbalance of BMP/TGFβ signalling contributes to endothelial dysfunction, vascular remodelling, inflammation and disordered angiogenesis in PAH. Additionally, we highlight how currently used drugs can influence BMP/TGFβ signalling. Finally, we browse the newly developed therapeutic approaches targeting BMPRII and TGFβ signalling pathways by focusing on preclinical studies and clinical trials and put them into perspectives.status: publishe

Possible influence of AMPD1 on cholinergic neurotransmission and sleep

It is known that adenosine excess due to monophosphate deaminase deficiency (AMPD1) can be linked to muscle problems. Recently, Perumal et al., 2014 reported a first case of possible impact of AMPD1 on sleep, REM sleep and cholinergic neurotransmission. We report a second patient with similar sleep complaints: long sleep duration with residual daytime sleepiness and a need to sleep after exercise. On polysomnography we observed a long sleep duration, with high sleep efficiency and a SOREMP; on MSLT a shortened sleep latency and 4 SOREMPS were observed. Frequency power spectral heart rate analysis during slow wave sleep, REM sleep and wakefulness revealed an increased parasympathetic tone. In conclusion, AMPD1 could have a profound influence on cholinergic neurotransmission and sleep; further studies are mandatory.status: publishe

Learning from registries in pulmonary arterial hypertension: pitfalls and recommendations

Pulmonary arterial hypertension is a rare and incurable chronic disease characterised by a progressive increase in pulmonary vascular resistance and right heart failure. Patient registries collecting observational data can be of great value in the understanding of clinical problems. While clinical trials provide data in selected patient populations, registries better depict real-life practice. This review aims to reflect the input of patient registries in the general knowledge of the disease. Advances in epidemiology of the different subgroups, including data on incidence and/or prevalence, increasing age at presentation and stagnating diagnostic delay are reported. The importance of haemodynamic definition criteria and cardiac comorbidities are underscored. The review also shows the major transformation that pulmonary arterial hypertension therapeutic management has undergone, with still insufficient use of combination therapies; consecutive improvement in outcome; upcoming evidence in disfavour of anticoagulation; and validity of the available risk-stratification tools derived from large registries. Product registries are also briefly presented. Finally, the benefits of registries and methodological aspects are discussed, including immortal time bias, registry data quality and recommendations from EU organisations (EUCERD and PARENT).status: publishe

Adherence to CPAP therapy: Comparing the effect of three educational approaches in patients with obstructive sleep apnoea

CPAP-therapy is the first-line treatment for moderate to severe obstructive sleep apnoea (OSA). A significant limitation of CPAP treatment is the poor therapy adherence, compromising the beneficial effects.status: publishe

Pulmonary arterial hypertension drugs can partially restore altered angiogenic capacities in bmpr2‐silenced human lung microvascular endothelial cells

Abstract Mutations in the bone morphogenetic protein receptor type 2 (bmpr2) gene and signaling pathway impairment are observed in heritable and idiopathic pulmonary arterial hypertension (PAH). In PAH, endothelial dysfunction is currently handled by drugs targeting the endothelin‐1 (ET‐1), nitric oxide (NO), and prostacyclin (PGI2) pathways. The role of angiogenesis in the disease process and the effect of PAH therapies on dysregulated angiogenesis remain inconclusive. We aim to investigate in vitro whether (i) bmpr2 silencing can impair angiogenic capacity of human lung microvascular endothelial cells (HLMVECs) and (ii) PAH therapies can restore them. The effects of macitentan (ET‐1), tadalafil (NO), and selexipag (PGI2), on BMPRII pathway activation, endothelial barrier function, and angiogenesis were investigated in bmpr2‐silenced HLMVECs. Stable bmpr2 silencing resulted in impaired migration and tube formation in vitro capacity. Inhibition of ET‐1 pathway was able to partially restore tube formation in bmpr2‐silenced HLMVECs, whereas none of the therapies was able to restore endothelial barrier function, no deleterious effects were observed. Our findings highlight the potential role of BMPRII signaling pathway in driving pulmonary endothelial cell angiogenesis. In addition, PAH drugs display limited effects on endothelial function when BMPRII is impaired, suggesting that innovative therapeutic strategies targeting BMPRII signaling are needed to better rescue endothelial dysfunction in PAH